Intranasal Delivery of Nerve Growth Factor in Neurodegenerative Diseases and Neurotrauma

Since the 1980s, the development of a pharmacology based on nerve growth factor (NGF)has been postulated for the therapy of Alzheimer's disease (AD). This hypothesis was basedon the rescuing effect of the neurotrophin on the cholinergic phenotype of the basal forebrainneurons, primarily compromised during the development of AD. Subsequently, the use ofNGF was put forward to treat a broader spectrum of neurological conditions affecting thecentral nervous system, such as Parkinson's disease, degenerative retinopathies, severebrain traumas and neurodevelopmental dysfunctions. While supported by solid rationalassumptions, the progress of a pharmacology founded on these hypotheses has beenhampered by the difficulty of conveying NGF towards the brain parenchyma withoutresorting to invasive and risky delivery methods. At the end of the last century, it wasshown that NGF administered intranasally to the olfactory epithelium was able to spread intothe brain parenchyma. Notably, after such delivery, pharmacologically relevant concentrationof exogenous NGF was found in brain areas located at considerable distances from theinjection site along the rostral-caudal axis. These observations paved the way for preclinicalcharacterization and clinical trials on the efficacy of intranasal NGF for the treatment ofneurodegenerative diseases and of the consequences of brain trauma. In this review, asummary of the preclinical and clinical studies published to date will be attempted, as well asa discussion about themechanisms underlying the efficacy and the possible development ofthe pharmacology based on intranasal conveyance of NGF to the brain.